期刊
ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
卷 1515, 期 1, 页码 196-207出版社
WILEY
DOI: 10.1111/nyas.14842
关键词
barrier function; claudin; HT-29/B6 cells; PI3K gamma; tight junction; TNF alpha; TER
资金
- Interdisciplinary Center for Clinical Research, University Hospital Jena
Phosphoinositide 3-kinases (PI3Ks) are enzymes that phosphorylate phospholipids in the cell membrane, promoting the PI3K/AKT signaling cascade. They play a significant role in various cellular functions, including TNF alpha-induced tight junction (TJ) impairment in inflammatory bowel diseases. This study focuses on the functional role of PI3K gamma in HT-29/B6 cells under inflammatory conditions. It is found that PI3K gamma deficiency protects the cells against TNF alpha-induced barrier dysfunction, independent of any PI3K activity.
Phosphoinositide 3-kinases (PI3Ks) are a family of enzymes phosphorylating phospholipids in the membrane, thereby, promoting the PI3K/AKT signaling cascade. PI3Ks are involved in a variety of fundamental cellular functions, including tumor necrosis factor alpha (TNF alpha)-induced tight junction (TJ) impairment-a hallmark of inflammatory bowel diseases. Most of the studies analyzing the role of class I PI3K signaling in epithelial barrier maintenance did not decipher which of the isoforms are responsible for the observed effects. By using wild-type and PI3K gamma-deficient HT-29/B6 cells, we characterized the functional role of PI3K gamma in these cells under inflammatory conditions. Measurement of the transepithelial electrical resistance and the paracellular flux of macromolecules revealed that monolayers of PI3K gamma-deficient cells, compared with wild-type cells, were protected against TNF alpha-induced barrier dysfunction. This effect was independent of any PI3K activity because treatment with a pan-PI3K inhibitor did not alter this observation. By immunostaining, we found correlative changes in the distribution of the TJ marker ZO-1. Furthermore, the absence of PI3K gamma reduced the basal level of the pore-forming TJ protein claudin-2. Our study suggests a novel noncanonical, kinase-independent scaffolding function of PI3K gamma in TNF alpha-induced barrier dysfunction.
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